Laboratory and clinical researchers at the University of Washington, the University of California at Davis, and the Fred Hutchinson Cancer Research Center, propose to establish a Fragile-X Research Center. Three interrelated molecular projects, one clinical research project, and one new core for patient recruitment and evaluation are proposed. The three projects with molecular biological and genetic emphases will examine epigenetic aspects of fragile-X syndrome: how methylation mosaicism can sometimes be compatible with transcription of the critical gene FMR1 (Laird); how delayed timing of replication of FMR1 during the cell cycle can contribute to transcriptional silencing of this gene (Hansen and Gartler); how chromatin surrounding FMR1 is organized so that transcriptional control signals are stable but influenced by the expanded triplet repeats and by methylation (Tapscott and Filippova). Together, these molecular studies will provide a new depth of analysis expected to reveal connections among chromatin structure, epigenetic modification of DNA, and control of timing of DNA replication, all of which have been implicated in the abnormal expression of the fragile-X gene, FMR1. The project with a clinical research focus will examine the role of anxiety in fragile-X patients, and the possible treatment of such anxiety (Hagerman). This investigation will seek to understand the relationships among anxiety, autonomic reactivity, clinical anxiety measures, and functional MRI patterns. In addition, sertraline will be used to treat anxiety and to study its effects on brain activation and on autonomic reactivity. Of special importance will be the examination of relationships among variations in the molecular parameters of FXS, autonomic reactivity, clinical aspects of anxiety, functional MRI measures, and various emotional and developmental tasks. The four projects are integrated by the opportunity to correlate molecular and clinical data to understand better the predictive value of the molecular parameters and their possible clinical relevance. [unreadable] [unreadable]